A variety of complex lipids are involved in the structure of biological membranes. These lipids can be classified into two categories, the glycerophospholipids and the sphingolipids. The sphingolipids or sphingoid bases, as they are commonly referred to, are natural, long-chain amino bases. They typically have a 2-amino-1,3-diol hydrophilic head and a long (usually 15-carbon), hydrophobic (lipophilic) alkyl chain. The amphiphlic nature of these biomolecules is responsible for their properties and function in the membrane, Liscovitch, M. et al, Biochem. Parmacol. 1991, 42, 2071-2075.
There is a link between sphingolipids and signal transduction. Shingoid bases have been shown to inhibit the protein kinase C, in vitro, Hannun, Y. et al, J. Biol. Chem. 1986, 261, 12604-12609, and thus the cellular responses mediated by protein kinase C, Nashizuka, Y., Science 1986, 223, 305-312; Bell, R. M., Cell 1986, 45, 631-632; Morrill, A. H., Jr. et al, Biochim Biophys. Acta 1989, 1010, 13-139. Sphingosine is one of the most potent inhibitors of the protein kinase C.
Recent SAR studies have revealed that inhibition is about the same with all of the major, naturally occurring long-chain bases, Hannun, Y. et al, J. Biol. Chem. 1986, 261, 12604-12609; Wilson, E. et al, J. Biol. Chem. 1986, 261, 12610-12614; and Merrill, A. H., Jr., et al, Biochemistry 1989, 28, 3138-3145; i.e., sphinganine (2, dihydrosphingosine) and 4-D-hydroxyphinganine (3, phytoshingosine). Key factors in the development of these sphingoid bases as inhibitors of the protein kinase C are: 1) they do not appear to affect most other kinases and 2) they are natural constituents of cells and tissues, Liscovitch, M. et al, Biochem. Parmacol. 1991, 42, 2071-2075. ##STR1##
Broadly the invention comprises the stereospecific syntheses of the dihidrosphingosines, which syntheses utilize certain chiral epoxides, set forth below, which chiral epoxides have been previously described, (a) Abushanab, E., U.S. Pat. No. 4,931,575; (b) Abushanab, E. et al, J. Org. Chem. 1988, 53, 2598-2602; (c) Vargeese, C. et al., J. Org. Chem. 1990, 55, 4400-4403. ##STR2##
The syntheses or processes of the invention comprise the steps, subsequent to step 4 in the reaction scheme shown in the FIGURE. The invention embodies all four isomers, where each chiral center can be R or S of compounds 6 through 14 shown in the FIGURE.